Despite the presence of HIV-1 in the oral cavity, transmission of the virus through saliva is rare which implicates innate/natural antiviral mechanisms for suppressing transmission. One such endogenous antiviral molecule, secretory leukocyte protease inhibitor (SLPI), inhibits HIV-1 infection of mononuclear cells during or soon after internalization. To further clarify the function of SLPI in innate/host defense, efforts are underway to generate mice homozygous for a null mutation of SLPI. In additional studies focusing on the regulation of HIV production after infection, opportunistic pathogens were shown to influence viral replication. By in situ hybridization, unprecedented levels of HIV were detected in co-infected tissues. Mycobacterium avium promotes HIV infection by activating the transcription factor NF-kappaB, stimulating cytokine and chemokine production and HIV co-receptor (CCR5) expression. The dynamic relationship between opportunistic pathogens, macrophages and high levels of viral replication emphasize that treatment of co-infections is important for controlling HIV production and plasma viremia, particularly in late-stage HIV-disease. In addition to opportunistic pathogens, mucosal inflammation also exacerbates HIV production and therapeutic intervention dramatically reduces viral burden, emphasizing the negative contribution of immune activation to the clinical course of AIDS.